A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Nature Genetics Année : 2011

A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease.

Mouloud Souidi
Jean-François Mosnier
  • Fonction : Auteur
Arlette Darfeuille-Michaud
  • Fonction : Auteur

Résumé

Susceptibility to Crohn's disease, a complex inflammatory disease, is influenced by common variants at many loci. The common exonic synonymous SNP (c.313C>T) in IRGM, found in strong linkage disequilibrium with a deletion polymorphism, has been classified as non-causative because of the absence of an alteration in the IRGM protein sequence or splice sites. Here we show that a family of microRNAs (miRNAs), miR-196, is overexpressed in the inflammatory intestinal epithelia of individuals with Crohn's disease and downregulates the IRGM protective variant (c.313C) but not the risk-associated allele (c.313T). Subsequent loss of tight regulation of IRGM expression compromises control of intracellular replication of Crohn's disease-associated adherent invasive Escherichia coli by autophagy. These results suggest that the association of IRGM with Crohn's disease arises from a miRNA-based alteration in IRGM regulation that affects the efficacy of autophagy, thereby implicating a synonymous polymorphism as a likely causal variant.
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Dates et versions

hal-00626157 , version 1 (23-09-2011)

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Citer

Patrick Brest, Pierre Lapaquette, Mouloud Souidi, Kevin Lebrigand, Annabelle Cesaro, et al.. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease.. Nature Genetics, 2011, 43 (3), pp.242-5. ⟨10.1038/ng.762⟩. ⟨hal-00626157⟩
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